Epilepsy is a major neurological disorder that affects all populations (W. Hauser et al., The prevalence of epilepsy in Rochester, Minn., 1940-80. Epilepsia 1991 32, 429-445). Epilepsy describes the types of recurrent seizures produced by paroxysmal excessive neuronal discharges in the brain (Evans, J. H. Post-traumatic epilepsy. Neurology 1962, 12, 665-674; Lindsay, J. M. Genetics and epilepsy. Epilepsia 1971, 12, 47-54). In the United States alone, some 2 million people suffer from epilepsy and its sequelae; 340,000 are children. For many individuals afflicted with epilepsy the disabilities and associated neuropsychological and behavioral factors limit the quality of life. The restrictions on patients with epilepsy plus the expense for treatment and rehabilitation result in a large cost to society (See, e.g., Begley, C. E.; Lairson, D. R.; Reynolds, T. F.; Coan, S. Early treatment cost in epilepsy and how it varies with seizure type and frequency. Epilepsia Res. 2001, 47, 205-215).
The mainstay of treatment for epileptic disorders has been the long-term and consistent administration of anticonvulsant drugs (See, e.g., McNamara, J. O. In: Goodman & Gilman's The Pharmacological Basis of Therapeutics, 10th Ed.; Hardman, J. G.; Limbird, L. E., Ed.; McGraw-Hill: New York, 2001; Ch. 21, pp. 521-547; Aiken, S. P.; Brown, W. M. Treatment of epilepsy: Existing therapies and future developments. Frontiers in Bioscience 2000, 5, 124-15). Unfortunately, current medications are ineffective for approximately one-third of patients with epilepsy (See, e.g., Bauer, J.; Reuber, M. Medical treatment of epilepsy. Expert Opinion on Emerging Drugs 2003, 8, 457-467). Many continue to have seizures, while others experience disturbing side effects (e.g., drowsiness, dizziness, nausea, liver damage) (Pellock, J. M.; Willmore, L. J. A rational guide to monitoring in patients receiving anticonvulsants. Neurology 1991, 41, 961-964). The shortcomings of current regimens highlight the need for new agents with novel mechanisms of action.